15 - Buprenorphine decreases hypoxia tolerance in the Vannucci model of hypoxia-ischemia in rats

N=50 postnatal day (P) 10 rats were randomized to receive 0.05 mg/kg buprenorphine or saline and underwent unilateral carotid artery ligation followed by a period of hypoxia (8% oxygen). Hypoxia was temperature-controlled (35.5°C target rectal temperature) and lasted up to three hours or up to 20% mortality, whichever occurred first. Animals were sacrificed on P13, and ex vivo percent area loss of the affected hemisphere was determined. Mortality and injury data were compared to a control cohort of N=83 from historical experiments who received 150min of hypoxia without buprenorphine use. A second cohort of N=48 rats randomized to buprenorphine or saline underwent hypoxia at a lower target temperature of 34.5°C.

Results: At a target rectal temperature of 35.5°C, hypoxia was terminated at 90min due to mortality – 28% and 4.0% in the buprenorphine and saline groups, respectively. The mortality in the buprenorphine group was significantly greater than in historical controls despite a 60min shorter hypoxia time (Table 1). In survivors, degree of injury (ipsilateral area loss) was significantly lower than historical controls (Figure 1). After decreasing intra-hypoxic temperature to 34.5°C and increasing hypoxia duration to 180 minutes, percent area loss among buprenorphine and saline animals was not significantly different from historical control animals (Figure 1).

Conclusion(s):

In the Vannucci model of HI in P10 rats, buprenorphine increased intra-hypoxic mortality, resulting in decreased hypoxia duration and brain injury in survivors. Lowering intra-hypoxic temperature from 35.5°C to 34.5°C and increasing hypoxia time to 180min decreased intra-hypoxic mortality and resulted in brain injury similar to previous experiments without buprenorphine. However, whether the same severity of injury responds similarly to therapies deserves future research as buprenorphine may alter the response to therapeutic interventions.